Cataract is an affliction of the lens of the eye. It is a very common problem in old age where it is referred to as senile cataract. Congenital cataract is generally found in young persons. A cataract is a partial or total opacity of the lens. Surgery, which involves removal of the lens, is generally a successful corrective means. The removal of the lens leaves primarily the cornea, to focus light upon the retina. This arrangement cannot provide sharp vision. However, use of contact lenses or glasses can provide a somewhat satisfactory substitute for the lens. The most common method of correcting this problem is to insert an intraocular artificial lens after removal of the cataract lens.
There remains a need for a therapeutic treatment of the lens which could prevent, or at least forestall, the development of cataracts. Advantageously, such a treatment could also be used for the reversal of cataracts. These desirable treatments are not now known in the art.
In order to possibly achieve such desirable treatments of the eye lens, the applicants have conducted extensive research on the nature of the lens itself. This research has led to some basic understanding of the eye lens as disclosed following.
Examination of normal and cataractous lenses indicates that while there is little oxidation in normal lenses, extensive oxidation occurs in a cataract, resulting in a high level of methionine oxidation to methionine sulfoxide and cysteine thiol oxidation to disulfide (Spector, A. and Roy, D. [1978] Proc. Natl. Acad. Sci. 75:3244-3248; Garner, M. H. and Spector, A. [1980] Proc. Natl. Acad. Sci. 77:1274-1277; Spector, A. [1984] Invest. Ophthal. & Vis. Sci. 25:130-146). Such oxidation occurs in the lens proteins, leading to the formation of disulfide linked high molecular weight aggregates which are capable of scattering light and producing a loss in lens transparency (Spector and Roy, 1978; Garner and Spector, 1980; Spector, A. Garner, M. H., Garner. W. H. Roy, D., Farnsworth, P. and Shyne, S. [1979] Science 204:1323-1326; Spector, A. and Garner, M. H. [1980] in developments in Biochemistry; Red Blood Cell and Lens Metabolism, S. K. Srivastava, ed., Vol. 9, pp. 233-236, Elsevier North-Holland, NY; Garner, M. H. and Spector, A. [1980] Exp. Eye Res. 31: 361-369). Some of these aggregates involve the linking, via disulfide bonds, of membrane components to components found within the cell (Spector and Garner, 1980; Garner and Spector, 1980; Garner, W. H., Garner, M. H. and Spector, A. [1981] Biochem. Biophys. Res. Comm. 98:439-447). The oxidation may also reduce or eliminate the activity of enzymes necessary for maintaining the viability of the tissue (Garner, W. H., Garner, M.H. and Spector, A. [1983] Proc. Natl. Acad. Sci. 80:2044-2048).
The lens is unique in having active metabolic activity and protein synthesis only in the outer region of the tissue. Thus, throughout much of the lens, oxidative insult to a protein molecule remains for the life of the tissue unless the insult can be repaired (Spector, A. [1984]Invest. Ophthal. & Vis. Sci. 25:130-146; Wannemacher, C. F. and Spector, A. [1968] Exp. Eye Res. 7:623-625; Dilley, K. J. and van Heyningen, R. [1976] Doc. Ophthalmol. Proc. Ser. 8:171; Hockwin, O and Ohrloff, C. [1981] In Molecular and Cellular Biology of the Eye Lens, H. Bloemendal, ed., p. 367, John Wiley & Sons, NY).
There are a number of systems that the lens employs to repair oxidative insult. For methionine sulfoxide, methionine sulfoxide peptide reductase is present which reduces the protein methionine sulfoxide back to methionine (Spector, A., Scotto, R., Weissbach, H. and Brot, N. [1982] Biochem. & Biophys. Res. Comm. 108:429-434; Brot, N., Weissbach, L., Werth, J. and Weissbach, H. [1981] Proc. Natl. Sci. 78:2155-2158; Brut, N. Werth, H. [1982] Anal. Biochem. 122:291-294). J., Koster, D. and Weissbach, This enzyme requires a dithiol as a co-factor reductant in order to function. It is believed that the physiological dithiol utilized is thioredoxin, a small protein of approximately 12,000 daltons (Spector, Scotto, Weissbach, Brot, 1982).
While a variety of systems are available to the cell to reduce disulfide bonds, protein disulfides are difficult to reduce and, generally, do not employ the same reducing systems as smaller components. Thus, for example, oxidized glutathione is reduced by glutathione reductase but this enzyme does not effectively reduce protein disulfides (Garner and Spector, 1980). Also, although it is known that thioredoxin and its co-factors thioredoxin reductase and nicotinamide adenine dinucleoside phosphate (NADPH) are capable of effectively reducing in vitro the disulfide bonds of a variety of proteins, including insulin and other protein disulfides, there has been no teaching or suggestion that such compounds can be used effectively in vivo.